In the past decade, inorganic nanocrystals, specifically gold nanoparticles (AuNPs) and semiconductor quantum dots (QDs), have generated great interest for applications in several areas of biology and medicine. See References 1 through 18. This stems from their unique sets of physical and chemical properties that exhibit size-, shape- and composition-dependence. For example, metallic AuNPs show size- and shape-dependent Surface Plasmon Resonance (SPR) absorption ranging from the visible to the near-infrared (NIR). See References 19 through 24. Similarly, some of the properties of semiconductor QDs including broad excitation, narrow and tunable emission across the visible and near-IR spectrum, high two-photon action cross-section and superior chemical stability account for their widespread applications as biological tagging and sensing agents. See References 3, 7, and 25 through 29. However, typical synthesis of high quality QDs (via “hot injection” routes) with narrow size distribution and control over size and core crystallinity provides nanocrystals that are capped with hydrophobic organic ligands. See References 30 through 36. These materials are exclusively soluble in hydrophobic solvents (such as toluene or hexane); this limits one's ability to integrate them with biomolecules, or introduce them into live cells. Therefore, an additional surface-modification with tailor-made ligands is required to render the nanocrystals stable in buffer media and biocompatible. See References 14 and 37 through 39.
Several strategies including silica coating, encapsulation, and ligand exchange have been reported for preparing biocompatible QDs. See References 40 through 53. Among those routes, ligand exchange which relies on the substitution of the native surface cap with hydrophilic coordinating ligands offers a few key advantages. This strategy is easy to implement and provides compact nanocrystals in aqueous media. It also permits easy introduction of specific reactive functionalities on the nanocrystal surfaces, for further modification with target biomolecules. See References 41, 45, 46, 49, and 54 through 57. Several modular ligands bearing thiol, amine, pyridine and imidazole as anchoring groups have been recently documented in the literature. See References 58 through 61. Among these, multidentate thiolated ligands, such as derivatives of dihydrolipoic acid (DHLA), provide enhanced colloidal stability of QDs (e.g., CdSe—ZnS) in aqueous media compared with those presenting monodentate coordinating groups, due to the strong affinity of thiol to the zinc-rich QD surface and higher coordination of dithiol groups. Over the past decade, a variety of DHLA-based ligands have been synthesized and tested, confirming the benefits of cooperative coordination onto the ZnS-overcoated QDs. See References 46, 50, 51, 60, and 62 through 65. The enhanced binding affinity of multithiol-appended ligands to AuNPs and AuNRs have also been reported. See References 66 through 68. To further exploit these effects, several groups have explored the possibility of using polymeric ligands instead, even though these can increase the hydrodynamic size of nanoparticles in buffer media. See References 41, 46, 48, 55, and 61. One of the challenges in designing the ligands (either polymeric or molecular scale) is the versatility and scalability of the synthetic scheme. Specifically, factors that need to be taken into consideration include the design of ligands with multiple functionalities and the use of versatile and scalable reaction schemes.
The following articles are referenced herein as if set forth in their entirety:
(1) Chan, W. C. W.; Nie, S. M. Science 1998, 281, 2016.
(2) Bruchez, M.; Moronne, M.; Gin, P.; Weiss, S.; Alivisatos, A. P. Science 1998, 281, 2013.
(3) Alivisatos, P. Nature Biotechnology 2004, 22, 47.
(4) Kim, S.; Lim, Y.; Soltesz, E.; De Grand, A.; Lee, J.; Nakayama, A.; Parker, J.; Mihaljevic, T.; Laurence, R.; Dor, D.; Cohn, L.; Bawendi, M.; Frangioni, J. Nature Biotechnology 2004, 22, 93.
(5) Michalet, X.; Pinaud, F.; Bentolila, L.; Tsay, J.; Doose, S.; Li, J.; Sundaresan, G.; Wu, A.; Gambhir, S.; Weiss, S. Science 2005, 307, 538.
(6) El-Sayed, I. H.; Huang, X. H.; El-Sayed, M. A. Nano Lett 2005, 5, 829.
(7) Medintz, I.; Uyeda, H.; Goldman, E.; Mattoussi, H. Nature Materials 2005, 4, 435.
(8) Chithrani, B. D.; Ghazani, A. A.; Chan, W. C. W. Nano Lett 2006, 6, 662.
(9) Huang, X. H.; El-Sayed, I. H.; Qian, W.; El-Sayed, M. A. J Am Chem Soc 2006, 128, 2115.
(10) Murphy, C. J.; Gole, A. M.; Stone, J. W.; Sisco, P. N.; Alkilany, A. M.; Goldsmith, E. C.; Baxter, S. C. Accounts of Chemical Research 2008, 41, 1721.
(11) Ghosh, P.; Han, G.; De, M.; Kim, C. K.; Rotello, V. M. Adv Drug Deliver Rev 2008, 60, 1307.
(12) You, C. J.; Wilmes, S.; Beutel, O.; Lochte, S.; Podoplelowa, Y.; Roder, F.; Richter, C.; Seine, T.; Schaible, D.; Uze, G.; Clarke, S.; Pinaud, F.; Dahan, M.; Piehler, J. Angewandte Chemie—International Edition 2010, 49, 4108.
(13) Pinaud, F.; Clarke, S.; Sittner, A.; Dahan, M. Nat Methods 2010, 7, 275.
(14) Mattoussi, H.; Palui, G.; Na, H. B. Adv Drug Deliver Rev 2012, 64, 138.
(15) Weintraub, K. Nature 2013, 495, S14.
(16) Cai, E.; Ge, P.; Lee, S. H.; Jeyifous, O.; Wang, Y.; Liu, Y.; Wilson, K. M.; Lim, S. J.; Baird, M. A.; Stone, J. E.; Lee, K. Y.; Davidson, M. W.; Chung, H. J.; Schulten, K.; Smith, A. M.; Green, W. N.; Selvin, P. R. Angewandte Chemie International Edition 2014, 53, 12484.
(17) Howes, P. D.; Chandrawati, R.; Stevens, M. M. Science 2014, 346.
(18) Rana, S.; Le, N. D. B.; Mout, R.; Saha, K.; Tonga, G. Y.; Bain, R. E. S.; Miranda, O. R.; Rotello, C. M.; Rotello, V. M. Nat Nanotechnol 2015, 10, 65.
(19) Mie, G. Ann Phys-Berlin 1908, 25, 377.
(20) Jana, N. R.; Gearheart, L.; Murphy, C. J. The Journal of Physical Chemistry B 2001, 105, 4065.
(21) Kelly, K. L.; Coronado, E.; Zhao, L. L.; Schatz, G. C. J Phys Chem B 2003, 107, 668.
(22) Gole, A.; Murphy, C. J. Chemistry of Materials 2005, 17, 1325.
(23) Liz-Marzan, L. M. Langmuir 2006, 22, 32.
(24) Jain, P. K.; Lee, K. S.; El-Sayed, I. H.; El-Sayed, M. A. The Journal of Physical Chemistry B 2006, 110, 7238.
(25) Jaiswal, J. K.; Mattoussi, H.; Mauro, J. M.; Simon, S. M. Nature Biotechnology 2003, 21, 47.
(26) C. B. Murray, C. R. K., M. G. Bawendi Ann. Rev. Mater. Sci. 2000, 30, 545.
(27) Talapin, D. V.; Lee, J. S.; Kovalenko, M. V.; Shevchenko, E. V. Chemical Reviews 2010, 110, 389.
(28) Resch-Genger, U.; Grabolle, M.; Cavaliere-Jaricot, S.; Nitschke, R.; Nann, T. Nat Meth 2008, 5, 763.
(29) Larson, D. R.; Zipfel, W. R.; Williams, R. M.; Clark, S. W.; Bruchez, M. P.; Wise, F. W.; Webb, W. W. Science 2003, 300, 1434.
(30) Talapin, D. V.; Rogach, A. L.; Komowski, A.; Haase, M.; Weller, H. Nano Lett 2001, 1, 207.
(31) Reiss, P.; Bleuse, J.; Pron, A. Nano Lett 2002, 2, 781.
(32) Peng, Z. A.; Peng, X. G. J Am Chem Soc 2001, 123, 183.
(33) Murray, C. B.; Norris, D. J.; Bawendi, M. G. J Am Chem Soc 1993, 115, 8706.
(34) Hines, M. A.; Guyot-Sionnest, P. Journal of Physical Chemistry 1996, 100, 468.
(35) Dabbousi, B. O.; Rodriguez Viejo, J.; Mikulec, F. V.; Heine, J. R.; Mattoussi, H.; Ober, R.; Jensen, K. F.; Bawendi, M. G. J Phys Chem B 1997, 101, 9463
(36) Reiss, P.; Protiere, M.; Li, L. Small 2009, 5, 154.
(37) Sapsford, K. E.; Algar, W. R.; Berti, L.; Gemmill, K. B.; Casey, B. J.; Oh, E.; Stewart, M. H.; Medintz, I. L. Chemical Reviews 2013, 113, 1904.
(38) Nam, J.; Won, N.; Bang, J.; Jin, H.; Park, J.; Jung, S.; Jung, S.; Park, Y.; Kim, S. Adv Drug Deliver Rev 2013, 65, 622.
(39) Tyrakowski, C. M.; Snee, P. T. Physical Chemistry Chemical Physics 2014, 16, 837.
(40) Liu, D.; Snee, P. T. ACS Nano 2011, 5, 546.
(41) Giovanelli, E.; Muro, E.; Sitbon, G.; Hanafi, M.; Pons, T.; Dubertret, B.; Lequeux, N. Langmuir 2012, 28, 15177.
(42) Yi, D. K.; Selvan, S. T.; Lee, S. S.; Papaefthymiou, G. C.; Kundaliya, D.; Ying, J. Y. J Am Chem Soc 2005, 127, 4990.
(43) Gerion, D.; Pinaud, F.; Williams, S. C.; Parak, W. J.; Zanchet, D.; Weiss, S.; Alivisatos, A. P. The Journal of Physical Chemistry B 2001, 105, 8861.
(44) Dubertret, B.; Skourides, P.; Norris, D. J.; Noireaux, V.; Brivanlou, A. H.; Libchaber, A. Science 2002, 298, 1759.
(45) Susumu, K.; Uyeda, H. T.; Medintz, I. L.; Pons, T.; Delehanty, J. B.; Mattoussi, H. J Am Chem Soc 2007, 129, 13987.
(46) Liu, W. H.; Greytak, A. B.; Lee, J.; Wong, C. R.; Park, J.; Marshall, L. F.; Jiang, W.; Curtin, P. N.; Ting, A. Y.; Nocera, D. G.; Fukumura, D.; Jain, R. K.; Bawendi, M. G. J Am Chem Soc 2010, 132, 472.
(47) Snee, P. T.; Somers, R. C.; Nair, G.; Zimmer, J. P.; Bawendi, M. G.; Nocera, D. G. J Am Chem Soc 2006, 128, 13320.
(48) Yildiz, I.; McCaughan, B.; Cruickshank, S. F.; Callan, J. F.; Raymo, F. M. Langmuir 2009, 25, 7090.
(49) Mei, B. C.; Susumu, K.; Medintz, I. L.; Delehanty, J. B.; Mountziaris, T. J.; Mattoussi, H. J Mater Chem 2008, 18, 4949.
(50) Uyeda, H. T.; Medintz, I. L.; Jaiswal, J. K.; Simon, S. M.; Mattoussi, H. J Am Chem Soc 2005, 127, 3870.
(51) Muro, E.; Fragola, A.; Pons, T.; Lequeux, N.; Ioannou, A.; Skourides, P.; Dubertret, B. Small 2012, 8, 1029.
(52) Palui, G.; Aldeek, F.; Wang, W. T.; Mattoussi, H. Chemical Society Reviews 2015, 44, 193.
(53) Pellegrino, T.; Manna, L.; Kudera, S.; Liedl, T.; Koktysh, D.; Rogach, A. L.; Keller, S.; Radler, J.; Natile, G.; Parak, W. J. Nano Lett 2004, 4, 703.
(54) Susumu, K.; Mei, B. C.; Mattoussi, H. Nature Protocols 2009, 4, 424.
(55) Yildiz, I.; Deniz, E.; McCaughan, B.; Cruickshank, S. F.; Callan, J. F.; Raymo, F. M. Langmuir 2010, 26, 11503.
(56) Muro, E.; Pons, T.; Lequeux, N.; Fragola, A.; Sanson, N.; Lenkei, Z.; Dubertret, B. J Am Chem Soc 2010, 132, 4556.
(57) Zhang, P.; Liu, S.; Gao, D.; Hu, D.; Gong, P.; Sheng, Z.; Deng, J.; Ma, Y.; Cai, L. J Am Chem Soc 2012, 134, 8388.
(58) Susumu, K.; Oh, E.; Delehanty, J. B.; Pinaud, F.; Gemmill, K. B.; Walper, S.; Breger, J.; Schroeder, M. J.; Stewart, M. H.; Jain, V.; Whitaker, C. M.; Huston, A. L.; Medintz, I. L. Chemistry of Materials 2014, 26, 5327.
(59) Wang, W.; Kapur, A.; Ji, X.; Safi, M.; Palui, G.; Palomo, V.; Dawson, P. E.; Mattoussi, H. J Am Chem Soc 2015, 137, 5438.
(60) Liu, W.; Howarth, M.; Greytak, A. B.; Zheng, Y.; Nocera, D. G.; Ting, A. Y.; Bawendi, M. G. J Am Chem Soc 2008, 130, 1274.
(61) Viswanath, A.; Shen, Y.; Green, A. N.; Tan, R.; Greytak, A. B.; Benicewicz, B. C. Macromolecules 2014, 47, 8137.
(62) Mattoussi, H.; Mauro, J. M.; Goldman, E. R.; Anderson, G. P.; Sundar, V. C.; Mikulec, F. V.; Bawendi, M. G. J Am Chem Soc 2000, 122, 12142.
(63) Gravel, E.; Tanguy, C.; Cassette, E.; Pons, T.; Knittel, F.; Bernards, N.; Garofalakis, A.; Duconge, F.; Dubertret, B.; Doris, E. Chemical Science 2013, 4, 411.
(64) Stewart, M. H.; Susumu, K.; Mei, B. C.; Medintz, I. L.; Delehanty, J. B.; Blanco-Canosa, J. B.; Dawson, P. E.; Mattoussi, H. J Am Chem Soc 2010, 132, 9804.
(65) Zhan, N.; Palui, G.; Grise, H.; Tang, H.; Alabugin, I.; Mattoussi, H. ACS Applied Materials & Interfaces 2013, 5, 2861.
(66) Oh, E.; Susumu, K.; Goswami, R.; Mattoussi, H. Langmuir 2010, 26, 7604.
(67) Chen, X. J.; Lawrence, J.; Parelkar, S.; Emrick, T. Macromolecules 2013, 46, 119.
(68) Mei, B. C.; Oh, E.; Susumu, K.; Farrell, D.; Mountziaris, T. J.; Mattoussi, H. Langmuir 2009, 25, 10604.
(69) Palui, G.; Avellini, T.; Zhan, N.; Pan, F.; Gray, D.; Alabugin, I.; Mattoussi, H. J Am Chem Soc 2012, 134, 16370.
(70) Zhan, N. Q.; Palui, G.; Safi, M.; Ji, X.; Mattoussi, H. J Am Chem Soc 2013, 135, 13786.
(71) Mei, B. C.; Susumu, K.; Medintz, I. L.; Mattoussi, H. Nature Protocols 2009, 4, 412.
(72) Isaacs, S. R.; Cutler, E. C.; Park, J. S.; Lee, T. R.; Shon, Y. S. Langmuir 2005, 21, 5689.
(73) Daniels, T. R.; Delgado, T.; Rodriguez, J. A.; Helguera, G.; Penichet, M. L. Clin Immunol 2006, 121, 144.
(74) Lowe, S. B.; Dick, J. A. G.; Cohen, B. E.; Stevens, M. M. Acs Nano 2012, 6, 851.
(75) Silvi, S.; Credi, A. Chemical Society Reviews 2015, 44, 4275.
(76) Medintz, I. L.; Stewart, M. H.; Trammell, S. A.; Susumu, K.; Delehanty, J. B.; Mei, B. C.; Melinger, J. S.; Blanco-Canosa, J. B.; Dawson, P. E.; Mattoussi, H. Nature Materials 2010, 9, 676.
(77) Chung, E. Y.; Ochs, C. J.; Wang, Y.; Lei, L.; Qin, Q.; Smith, A. M.; Strongin, A. Y.; Kamm, R.; Qi, Y.-X.; Lu, S.; Wang, Y. Nano Lett 2015, 15, 5025.
(78) Mattoussi, H.; Cumming, A. W.; Murray, C. B.; Bawendi, M. G.; Ober, R. Phys Rev B 1998, 58, 7850.
(79) Leatherdale, C. A.; Woo, W. K.; Mikulec, F. V.; Bawendi, M. G. J Phys Chem B 2002, 106, 7619.
(80) Clapp, A. R.; Medintz, I. L.; Mauro, J. M.; Fisher, B. R.; Bawendi, M. G.; Mattoussi, H. J Am Chem Soc 2004, 126, 301.
(81) Palui, G.; Na, H. B.; Mattoussi, H. Langmuir 2012, 28, 2761.
(82) Susumu, K.; Oh, E.; Delehanty, J. B.; Blanco-Canosa, J. B.; Johnson, B. J.; Jain, V.; Hervey, W. J.; Algar, W. R.; Boeneman, K.; Dawson, P. E.; Medintz, I. L. J Am Chem Soc 2011, 133, 9480.
(83) Yu, W. W.; Peng, X. G. Angewandte Chemie—International Edition 2002, 41, 2368.
(84) Ojea-Jimenez, I.; Garcia-Fernandez, L.; Lorenzo, J.; Puntes, V. F. ACS Nano 2012, 6, 7692.
(85) Schnolzer, M.; Alewood, P.; Jones, A.; Alewood, D.; Kent, S. B. H. Int J Pept Prot Res 1992, 40, 180.